Compelling evidence from model systems points to immune surveillance mechanisms that can recognize and eliminate tumor cells (Smyth et al., 2001, Int. Immunol. 13:459-463; Shankaran et al., 2001, Nature 410:1107-1111; Qin, 2009, Cell. Mol. Immunol. 6:3-13). Yet, established cancers commonly resist immune eradication, attributable in part to immunosuppressive elements within tumor microenvironments that limit the anti-tumor activity of infiltrating CD8+ cytotoxic T lymphocytes (CTL) and other immune effectors. A variety of immunosuppressive mechanisms have been suggested to date, including tumor-intrinsic events (e.g., down-regulation of costimulators), soluble suppressive factors (e.g., transforming growth factor β), and regulatory cells capable of actively inhibiting effector T cell (Teff) responses (e.g., FoxP3+ regulatory T cells (Treg) and myeloid-derived suppressor cells) (Shevach, 2009, Immunity 30: 636-645; Teicher, 2009, Biochem. Pharmacol. 77:1665-1673). With respect to the latter, the balance between regulatory and effector T cell activities within tumor beds has emerged as a critical determinant of the efficacy of anti-tumor immune responses (Yamaguchi and Sakaguchi, 2006, Semin Cancer Biol. 16:115-123; Miller et al., 2006, J. Immunol. 177:7398-7405; Gao et al., 2007, J. Clin. Oncol. 25:2586-2593; Bates et al., 2006, J. Clin. Oncol. 24: 5373-5380; Oble et al., 2009, Cancer. Immun 9:3). In turn, this insight beckons new cancer immunotherapeutic strategies designed to tip the Treg:Teff balance away from inhibition and towards activation.
An ideal therapeutic would in fact be one that could simultaneously inhibit Treg and activate Teff cells. In developing strategies for coordinate modulation of Treg and Teff cells, two costimulator receptors of the tumor necrosis family receptor (TNFR) superfamily are of special interest—GITR (glucocorticoid-induced TNFR family-related gene) and OX40. Each of these surface receptors is transiently up-regulated on activated Teff cells, and interestingly, each is also expressed constitutively on Treg cells, with further induction upon activation (Ishii et al., 2010, Adv. Immunol. 105:63-98; Nocentini et al., 2007, Eur. J. Immunol. 37:1165-1169). Furthermore, both GITR and OX40 promote CD4+ and CD8+ T cell survival, proliferation and effector functions and abrogate Treg cell suppressive effects (Shimizu et al., 2002, Nat. Immunol. 3:135-142; Piconese et al., 2008, J. Exp. Med. 205:825-839; Ji et al., 2004, J. Immunol. 172:5823-5827; Vu et al., 2007, Blood 110:2501-2510; Cohen et al., 2010, PLoS One 5:e10436; van Olffen et al., 2009, J. Immunol. 182:7490-7500). Hence, the triggering of either receptor should in principle allow simultaneous modulation of both T cell classes. While this dual Treg/Teff modulatory potential could theoretically explain, at least in part, the documented anti-tumor efficacy of agonistic therapeutic mAb directed at the GITR and OX40 receptors (Piconese et al., 2008, J. Exp. Med. 205:825-839; Zhou et al., 2007, J. Immunol. 179:7365-7375; Ko et al., 2005, J. Exp. Med. 202:885-891; Burocchi et al., 2011, Eur. J. Immunol. 41:3615-3626; Kitamura et al., 2009, Int. J. Cancer 125:630-638), no studies to date have formally demonstrated this causal link. Another unexplored question is whether therapeutic synergies might be achieved by co-triggering the OX40 and GITR receptors, given that each manifests analogous effects on both Teff and Treg cells.
Thus, there is a need in the art for new cancer immunotherapeutic treatments based on the coordinate modulation of Treg and Teff cells. The present invention addresses this unmet need in the art.